Novel formulations comprising lipid-regulating agents

ABSTRACT

The present invention is directed to a formulation comprising a lipid-regulating agent dissolved in at least one monoglyceride as the primary solvent medium for said agent. One or more emulsifiers may be added to the formulation.

FIELD OF THE INVENTION

[0001] The present invention relates to novel formulations for oraladministration comprising lipid-regulating agents.

BACKGROUND OF THE INVENTION

[0002] 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid,1-methylethylester, also known as fenofibrate, is representative of abroad class of compounds having pharmaceutical utility as lipidregulating agents. More specifically, this compound is part of alipid-regulating agent class of compounds commonly known as fibrates,and is disclosed in U.S. Pat. No. 4,058,552.

[0003] Fenofibrate has been prepared in several different formulations,c.f., U.S. Pat. Nos. 4,800,079 and 4,895,726. U.S. Pat. No. 4,895,726discloses a co-micronized formulation of fenofibrate and a solidsurfactant.

[0004] U.S. Pat. No. 4,961,890 discloses a process for preparing acontrolled release formulation containing fenofibrate in an intermediatelayer in the form of crystalline microparticles included within pores ofan inert matrix. The formulation is prepared by a process involving thesequential steps of dampening said inert core with a solution based onsaid binder, then projecting said fenofibrate microparticles in a singlelayer onto said dampened core, and thereafter drying, before saidsolution based on said binder dissolves said fenofibrate microparticles,and repeating said three steps in sequence until said intermediate layeris formed.

[0005] European Patent Application No. EP0793958A2 discloses a processfor producing a fenofibrate solid dosage form utilizing fenofibrate, asurface active agent and polyvinyl pyrrolidone in which the fenofibrateparticles are mixed with a polyvinyl pyrrolidone solution. The thusobtained mixture is granulated with an aqueous solution of one or moresurface active agents, and the granulate thus produced is dried.

[0006] PCT Publication No. WO 82/01649 discloses a fenofibrateformulation having granules that are comprised of a neutral core that isa mixture of saccharose and starch. The neutral core is covered with afirst layer of fenofibrate, admixed with an excipient and with a secondmicroporous outer layer of an edible polymer.

[0007] U.S. Pat. No. 5,645,856 describes the use of a carrier forhydrophobic drugs, including fenofibrate, and pharmaceuticalcompositions based thereon. The carrier comprises a digestible oil and apharmaceutically-acceptable surfactant component for dispersing the oilin vivo upon administration of the carrier, which comprises ahydrophilic surfactant, said surfactant component being such as not tosubstantially inhibit the in vivo lipolysis of the digestible oil.

[0008] Gemfibrozil is another member of the fibrate class oflipid-regulating agents. U.S. Pat. No. 4,927,639 discloses adisintegratable formulation of gemfibrozil providing both immediate andsustained release, comprising a tablet compressed from a mixture of afirst and second granulation, and a disintegration excipient operable toeffect partial or complete disintegration in the stomach. The firstgranulation comprises finely divided particles of pure gemfibrozilgranulated with at least one cellulose derivative, and the secondgranulation comprises finely divided particles of pure gemfibrozilgranulated with a pharmaceutically-acceptable water soluble or insolublepolymer which are then uniformly coated with apharmaceutically-acceptable (meth)acylate copolymer prior to admixturewith the first granulation. The first and second granulations arepresent in the final composition in a ratio of from about 10:1 to about1:10.

[0009] U.S. Pat. No. 4,925,676 discloses a disintegratable gemfibroziltablet providing both immediate and enteric release, which is compressedfrom a mixture of a first granulation of gemfibrozil with at least oneacid-disintegratable binder, and a second granulation formed from thefirst granulation, but regranulated or coated with analkali-disintegratable formulation of at least one substantiallyalkali-soluble and substantially acid-insoluble polymer.

[0010] Another class of lipid-regulating agents are commonly known asstatins, of which pravastatin and atorvastatin are members. U.S. Pat.Nos. 5,030,447 and 5,180,589 describe stable pharmaceuticalcompositions, which when dispersed in water have a pH of at least 9, andinclude a medicament which is sensitive to a low pH environment, such asprevastatin, one or more fillers such as lactose and/or microcrystallinecellulose, one or more binders, such as microcrystalline cellulose (drybinder) or polyvinyl pyrrolidone (wet binder), one or moredisintegrating agents such as croscarmellose sodium, one or morelubricants such as magnesium stearate and one or more basifying agentssuch as magnesium oxide.

[0011] It is an object of the present invention to provide formulationsfor oral administration comprising lipid-regulating agents havingenhanced bioavailability when compared to commercially availableformulations.

SUMMARY OF THE INVENTION

[0012] The present invention is directed to a formulation comprising alipid-regulating agent, and further comprising at least onemonoglyceride as the primary solvent medium for said agent. One or moreemulsifiers may be added to the formulation.

[0013] The formulation may be administered directly, diluted into anappropriate vehicle for administration, encapsulated into soft or hardgelatin shells or capsules for administration, or administered by othermeans obvious to those skilled in the art.

BRIEF DESCRIPTION OF THE DRAWINGS

[0014]FIG. 1 is a graph showing the plasma concentration in fasted dogsof the formulation of Example 1 and a reference composition.

DETAILED DESCRIPTION OF THE INVENTION

[0015] The bulk lipid-regulating agent can be prepared by any availablemethod, as for example the compound fenofibrate may be prepared by theprocedure disclosed in U.S. Pat. No. 4,058,552 or the proceduredisclosed in U.S. Pat. No. 4,739,101, both herein incorporated byreference.

[0016] Representative monoglycerides include, but are not limited to,glyceryl oleate (Capmul GMO-K™, Abitec), glyceryl caprylate/caprate(Capmul MCM, Abitec), glyceryl caprylate (Capmul MCMC8, Abitec), andglyceryl caprate (Capmul MCMC10, Abitec). A preferred monoglyceride isglyceryl oleate.

[0017] Suitable emulsifiers include pharmaceutically-acceptablesurfactants such as, for example, TPGS (d-alpha Tocopheryl PolyethyleneGlycol 1000 Succinate), phospholipids, polyoxyethylene sorbitan fattyacid derivatives, castor oil or hydrogenated castor oil ethoxylates,polyglycerol esters of fatty acids, fatty acid ethoxylates, alcoholethoxylates, polyoxyethylene-polyoxypropylene co-polymers and blockco-polymers. Preferred emulsifiers include castor oil or hydrogenatedcastor oil ethoxylates. A more preferred emulsifier is Cremophor EL™, apolyoxyl 35 castor oil, available from BASF.

[0018] Other optional ingredients which may be included in thecompositions of the present invention are those which are conventionallyused in oil-based drug delivery systems, e.g. antioxidants such as, forexample, tocopherol, ascorbyl palmitate, ascorbic acid, butylatedhydroxytoluene, butylated hydroxyanisole, propyl gallate, etc.; pHstabilisers such as, for example, citric acid, tartaric acid, fumaricacid, acetic acid, glycine, arginine, lysine, potassium hydrogenphosphate, etc.; thickeners/suspending agents such as, for example,hydrogenated vegetable oils, beeswax, colloidal silicone dioxide, gums,celluloses, silicates, bentonite, etc.; flavoring agents such as cherry,lemon, aniseed flavors, etc.; sweeteners such as aspartame, saccharin,cyclamates, etc.; and co-solvents such as, for example, ethanol,propylene glycol, dimethyl isosorbide, etc.

[0019] The solution comprising the lipid-regulating agent is prepared bydissolving said agent in the monoglyceride with adequate mixing at atemperature sufficient to liquefy the monoglyceride. If an emulsifier isused, it is added to the monoglyceride with mixing prior to addition ofthe lipid-regulating agent.

[0020] The resulting premix liquid comprising the lipid-regulating agentmay be dosed directly for oral administration, diluted into anappropriate vehicle for oral administration, filled into soft or hardgelatin capsules for oral administration, or delivered by some othermeans obvious to those skilled in the art. The premix liquid can be usedto improve the oral bioavailability, and/or increase the solubility ofsaid agent.

[0021] The invention will be understood more clearly from the followingnon-limiting representative examples.

EXAMPLE 1

[0022] Capmul GMO-K (Abitec) (8.0 gm) was heated to approximately 40 C.until it was liquefied and added to a scintillation vial. Ethanol USP,200 proof (1.3 gm) was added to the vial, heated to 50-60 C. in a waterbath and mixed until it was uniform. Fenofibrate (0.7 gm) was then addedto the vial and mixed until it was completely dissolved. 957 mg. of thepremix (containing 67 mg. fenofibrate) was added to each of six softgelatin capsules using a syringe. The capsules were heat-sealed andstored.

EXAMPLE 2

[0023] Capsules prepared by the process described in Example 1 and froma commercial fenofibrate composition, Lipanthyl 67M (Groupe Fournier)(reference) were administered to a group of six fasted dogs at a dose of67 mg/dog (one capsule per dog). The plasma concentrations of fenofibricacid were determined by HPLC. Concentrations were normalized to a 6.7mg/kg dose in each dog. FIG. 1 presents the resulting data in graphform.

1. A composition comprising a lipid-regulating agent dissolved in atleast one monoglyceride.
 2. A composition of claim 1 wherein thelipid-regulating agent is a fibrate.
 3. A composition of claim 2 whereinthe fibrate is fenofibrate.
 4. A composition of claim 1 wherein at leastone or more of the monoglycerides is selected from glyceryl oleate,glyceryl caprylate/caprate, glyceryl caprylate, and glyceryl caprate. 5.A composition of claim 4 wherein the monoglyceride is glyceryl oleate.6. A composition as in claim 1 further comprising at least oneemulsifier.
 7. A composition of claim 6 wherein at least one emulsifieris selected from castor oil or hydrogenated castor oil ethoxylates.
 8. Acomposition of claim 7 wherein the castor oil or hydrogenated castor oilethoxylates is a polyoxyl 35 castor oil.
 9. A composition of claim 1that contains a therapeutically-effective amount of a lipid-regulatingagent.
 10. A composition of claim 9 wherein the lipid-regulating agentis a fibrate.
 11. A composition of claim 10 wherein the fibrate isfenofibrate.
 12. A capsule comprising a composition of claim 1 .
 13. Acapsule of claim 12 wherein the lipid-regulating agent is a fibrate. 14.A capsule of claim 13 wherein the fibrate is fenofibrate.
 15. A methodof treating hyperlipidemia comprising the administration of acomposition of claim 1 to a patient.
 16. A method of treatinghyperlipidemia comprising the administration of a composition of claim 9to a patient.
 17. A method of claim 16 wherein the lipid-regulatingagent is a fibrate.
 18. A method of claim 17 wherein the fibrate isfenofibrate.
 19. A composition of claim 1 further comprising at leastone co-solvent.
 20. A composition of claim 19 wherein at least oneco-solvent is selected from ethanol, propylene glycol, and dimethylisosorbide.